ObjectiveTo explore the mechanism of Chenpi Huoxiangtang against diarrhea based on network pharmacology and experimental verification. MethodThe active components and targets of Chenpi Huoxiangtang were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and targets related to diarrhea from GeneCards and Online Mendelian Inheritance in Man （OMIM）. Thereby， the common targets were screened out. The component-target-disease network and protein-protein interaction （PPI） network were constructed with Cytoscape 3.7.1 and STRING. Bioconductor and R language were employed for gene ontology （GO） term enrichment and Kyoto encyclopedia of genes and genomes （KEGG） pathway enrichment of core targets， and AutoDockTools 1.5.6 and AutoDockVina 1.1.2 for molecular docking. Finally， animal experiment was carried out for verification. ResultA total of 51 active components 226 targets of Chenpi Huoxiangtang and 37 common targets of the medicine and the disease were screened out. The core targets were involved in 1 249 GO terms （P<0.05） and 110 KEGG pathways （P<0.05）， mainly the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）， Janus kinase （JAK）/signal transducer and activator of transcription （STAT）， hypoxia inducible factor （HIF）-1， and mitogen-activated protein kinase （MAPK） pathways. Molecular docking suggested that hesperidin and Akt1 showed the highest binding affinity. Animal experiment demonstrated that Chenpi Huoxiangtang significantly alleviated the diarrhea symptoms. The diarrhea index on the first day of administration decreased to 0.92， which was statistically different from that （1.24） of the model group （P<0.05）. The intestinal ink propulsion rate was 70.36%， higher than that （58.20%） in the model group （P<0.01）. Moreover， intestinal peristalsis was improved by the decoction. Enzyme-linked immunosorbent assay （ELISA） indicated the decrease in the levels of interleukin-6 （IL-6） and interleukin-1β （IL-1β） （P<0.05） and increase in the levels of Akt1， epidermal growth factor （EGF）， and epidermal growth factor receptor （EGFR） （P<0.05）. ConclusionThe active components of Chenpi Huoxiangtang mainly regulate PI3K/Akt， MAPK， and other signaling pathways through Akt1， IL-6， IL-1β， EGF， EGFR， and other core targets， thereby relieving diarrhea. This study is expected to lay a basis for the research on the pharmacological mechanism of Citri Reticulatae Pericarpium-Pogostemonis Herba combination and the scientific connotation of their compatibility.